Download LESSON 4.3 WORKBOOK What makes us go to sleep, and what

LESSON 4.3 WORKBOOK
What makes us go to sleep, and what
makes us wake up?
DEFINITIONS OF TERMS
Arousal neurons – neurons
located in the brainstem that
when active keep us awake and
alert.
Ventrolateral preoptic nucleus
(VLPO) – nucleus in the
hypothalamus that when active,
puts us to sleep.
So far we’ve discussed the nature of sleep, its functions, and problems associated with it. Now, let’s
examine what researchers have discovered about the
neural circuits that are responsible for sleep and its
counterpart, alert wakefulness.
Control of the sleep-wake cycle
The length of time we’ve been awake and active
The time of day
The Flip-Flop Switch
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 4.3
When we are awake and alert, most of the neurons in our brain – especially those in our forebrain – are
active, which enables us to pay attention to sensory information, to think about what we are perceiving,
to retrieve and think about memories, and to engage in the variety of behaviors that we have to do during
the day. The level of brain activity is largely controlled by the arousal neurons located in our brainstem
(Figure 12). A high level of activity of these neurons keeps us awake, and a low level puts us to sleep.
But what controls the activity of the
arousal neurons? What causes this
activity to fall, and put us to sleep? We
know that a region of the hypothalamus,
usually referred to as the ventrolateral
preoptic nucleus (VLPO), is critically
important for controlling when we fall
asleep (Figure 12). If this area is destroyed total insomnia results. On the
other hand, stimulating this area electrically can induce sleep.
Areas in the hypothalamus put us to sleep VLPO (Sleep neurons) ___________________________________
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What area of the brain is responsible for putting us to sleep?
Our sleep-wake cycles are controlled by two main factors:
•
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What area of the brain is responsible for
keeping us awake and alert?
Areas in the brainstem keep us awake Arousal Neurons Figure 12: Neural control of sleep and wakefulness.
Arousal neurons in the brainstem keep us awake. VLPO
neurons in the hypothalamus put us to sleep.
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LESSON READING
The VLPO contains sleep neurons. Their axons form inhibitory synaptic connections with the brain’s
arousal neurons, and inhibit them. When our VLPO sleep neurons become active and suppress the activity of our arousal neurons, we fall asleep. The sleep neurons in the VLPO themselves receive inhibitory
inputs from some of the same regions they inhibit, including the arousal neurons in the brainstem. Thus,
when arousal neurons are active, they inhibit the VLPO sleep neurons and we remain awake. It is important to understand that the VLPO sleep neurons need to be active to inhibit the arousal neurons and vice
versa – inhibition is an active process, just like excitation.
DEFINITIONS OF TERMS
Orexin neurons – neurons
located in the hypothalamus that
use the neurotransmitter orexin.
When active, these neurons
activate the arousal neurons in
our brainstem to keep us awake.
Damage to these neurons has
been implicated in narcolepsy.
For a complete list of defined
terms, see the Glossary.
The fact that the sleep neurons inhibit
the arousal neurons and vice versa is
called a flip-flop switch that sets periods of sleep and waking. As you might
imagine the flip-flop switch can only be
in one of two states ‘on’ or ‘off’. If the
sleep neurons are active and inhibit the
arousal neurons we will be asleep. Conversely, if the arousal neurons are active
and inhibit the sleep neurons, we are
awake (Figure 13). Also because the
two switches are mutually inhibitory, it is
impossible for the neurons in both sets
of regions to be active at the same time.
A. During wakefulness B. During sleep Figure 13: The flip-flop
switch. The VLPO and
the arousal neurons are
connected to each other
by inhibitory neurons.
(A) When the arousal
neurons are active, they
inhibit the VLPO and we
remain awake. (B) When
the VLPO neurons are
active, they inhibit the
arousal neurons and we
fall asleep.
A flip-flop switch has one important advantage – when it switches from one state to another, it does so
quickly. Clearly, it is to our advantage to be either asleep or awake. A state that has some of the characteristics of both sleep and wakefulness would be quite problematic!
Controlling the switch
There is one problem with flip-flop switches however – they can be unstable. In fact, people with narcolepsy exhibit just this characteristic. They have difficulty staying awake and they also have trouble remaining asleep for an extended amount of time.
Wo r k b o o k
Lesson 4.3
We know from examining animals with narcolepsy that the problem lies in damage to a set of neurons
called orexin neurons. The orexin neurons are located in the hypothalamus and are so named because
they use the neurotransmitter orexin. Orexin neuron are connected to the arousal neurons in the brainstem
and help stabilize the sleep-wake flip-flop switch (Figure 14).
How do these two areas connect? What type
of synapse do these two areas make with
each other?
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What neurons help to stabilize the flip-flop
switch?
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LESSON READING
How do orexin neurons connect to the flipflop switch?
Figure 14: The orexin
neurons. Orexin neurons
in the hypothalamus send
projections to the arousal
neurons in the brainstem
to further control the flipflop switch regulating our
sleep-wake circuit.
But how do orexin neurons stabilize the flip-flop switch? Orexin neurons are activated by light, energy
balance, and the limbic system (which you’ll remember regulates emotion). These inputs cause the orexin
neurons to activate the arousal neurons, tipping the activity of the flip-flop switch toward the waking state,
thus promoting wakefulness and inhibiting sleep. When input to the orexin neurons from light, energy balance and limbic system stops, the orexin neurons stop activating the arousal neurons. Now the balance is
shifted, allowing the VLPO sleep neurons to inhibit the arousal neurons, thus promoting sleep and inhibiting wakefulness (Figure 15).
A. During wakefulness B. During sleep Wo r k b o o k
Lesson 4.3
Figure 15: The orexin neurons
are the actual switch between
being awake and being asleep.
(A) When orexin neurons are
stimulated by light, emotional
cues or energy balance they
activate the arousal neurons,
which in turn inhibit the VLPO
and we remain awake. (B)
When input to the orexin neurons from light, energy balance
and limbic system stops, the
orexin neurons stop activating the arousal neurons. Now
the balance is shifted and the
VLPO can inhibit the arousal
neurons and we fall asleep.
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What turns orexin neurons on? What turns
them off?
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LESSON READING
What causes narcolepsy?
So what causes narcolepsy?
Narcolepsy is a relatively uncommon condition — only one case per 2,500 people — but it is a great
example of a defect in the flip-flop switch that controls the transition between wakefulness and sleep,
particularly REM sleep.
Narcoleptics have sleep attacks during the day, in which they
suddenly fall asleep. This is socially disruptive, as well as dangerous — for example, if it strikes while they are driving. They
tend to enter REM sleep very quickly, and may even enter a
dreaming state while still partially awake. They also have attacks during which they lose muscle tone — similar to what
occurs during REM sleep only while they are awake. These
attacks of paralysis, known as cataplexy, can be triggered by
emotional experiences, even by hearing a funny joke.
You can watch a profile of a patient with narcolepsy online —
see this unit on the student website or click below:
■■ Video: Narcolepsy
Figure 16: Defects in orexin signaling
cause narcolepsy. If orexin input to
the arousal neurons doesn’t occur,
wakefulness and sleep are no longer
carefully controlled and people
transition uncontrollably from one to
the next.
Narcolepsy has been traced to defects in the orexin neurons
(Figure 16). For instance, two dog species that have narcolepsy naturally have an abnormality in the gene
that will make a receptor for the orexin neurotransmitter. Also, if we remove the gene for orexin from mice,
they immediately become narcoleptic. These mice also move directly from wakefulness to REM sleep –
which is also a characteristic of patients with narcolepsy (Figure 17). Since signaling between the orexin
neurons and the arousal neurons requires both the orexin neurotransmitter and the orexin receptors on
the arousal neurons that recognize the transmitter, removing either of the two partners in orexin signaling
between the neurons can cause narcolepsy.
Wo r k b o o k
Lesson 4.3
Figure 17: Narcoleptic mice. Normal mice
are called wild-type (top). When they fall
asleep they move through the stages of
sleep until they enter REM sleep. When
the orexin receptor is removed from
the mice by genetic engineering, this is
called Orexin-knockout (right). Orexin
knockout mice become narcoleptic, transitioning from wakefulness to sleep many
times a day. Sometimes they transition
directly from wakefulness to REM sleep
(indicated by the small arrovheads).
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LESSON READING
How did scientists realize that the orexin neurons were affected in narcoleptic humans?
Human cases of narcolepsy also
show problems with the orexin signaling pathway, and have abnormally low
orexin levels in the brain and spinal fluid.
However human patients don’t have the
genetic defects we saw in the dogs. Humans develop the disorder in their teens
or 20s, and we think its because the immune system attacks the orexin neurons
(like we saw in multiple sclerosis). Using
brain tissues postmortem (after people
have died), researchers have shown
that humans with narcolepsy have far
fewer orexin neurons than humans without narcolepsy (Figure 18).
Figure 18: Narcolepsy in humans is triggered by
actual loss of orexin containing neurons in the
hypothalamus. The pictures are data from normal
patients (left panel) and narcoleptic patients (right
panel). The pictures are of brain tissue after the
orexin neurons have been marked with an antibody
against them. Then the antibody itself is marked
with a dark brown color. The dark brown spots represent neurons that contain orexin. The narcoleptic
patient has far fewer orexin containing neurons than
the control patient.
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You can watch a video of a narcoleptic dog online — see this unit on the student website or click below:
Wo r k b o o k
Lesson 4.3
■■ Video: Snoozy the Narcoleptic Dog!
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STUDENT RESPONSES
Given what you know about the causes of narcolepsy, how do you think you could treat the disorder?
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Wo r k b o o k
Lesson 4.3
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